A key challenge in moving from a genetic understanding of disease to effective therapeutics is the identification of functionally validated effectors of the process, against which small molecule inhibitors can be developed. The challenge in the case of acute lymphoblastic leukemia (ALL) is that such effectors are not known. The drug discovery challenge in ALL is compounded by the fact that ALL does not represent an attractive market for industry, thus shifting the burden of early chemical discovery to academia. We propose here a chemical genomic solution whereby a small molecule screen is performed based on the ability of compounds to modulate a gene expression program of interest. This is based on our recently reported Gene Expression-Based High Throughput Screening (GE-HTS) method wherein we demonstrated that we could identify small molecules capable of inducing myeloid differentiation of AML cells based on their ability to trigger a gene expression signature of interest. We now propose to extend this approach to three important areas of ALL biology. In Aim 1, we will define a gene expression signature of TEL/AML1 activity, and we will attempt to identify compounds capable of reversing the TEL/AML1 gene expression program. Such compounds would be a starting point for molecularly targeted therapy for TEL/AML1 positive patients. In Aim 2, we will similarly attempt to identify compounds capable of reversing the molecular program of MLL mutation as a means of exploring therapeutic approaches for MLL-rearranged leukemias. Lastly, in Aim 3 we will screen for chemicals capable of modulating glucocorticoid sensitivity in ALL cells. Such molecules would have great utility both as biological tool compounds with which to better understand the biology of glucocorticoid sensitivity, and may also suggest therapeutic strategies for ALL patients unlikely to respond to standard therapy.